Mycoplasmas are the smallest self-replicating microorganisms and have unique properties among the prokaryotes, such as (i) their need for cholesterol to maintain their membrane envelope and (ii) the absence of an external wall. Mycoplasmas are known to cause pulmonary infection in humans. See, Razin et al., “Molecular biology and pathogenicity of mycoplasmas,” Microbiol, and Molecular Biology Review; 62(4): 1094-1156, (1998). Furthermore, it is widely known that mycoplasmas can cause disease in most animals, including animals of commercial importance to the husbandry industry, such as cattle, swine, and fowl. See, Maniloff et al. Eds., Mycoplasmas, Molecular Biology and Pathogenesis, American Society for Microbiology (Washington, 1992).
It has been suggested that mycoplasma may play a role in the pathogenesis of a number of other diseases, including asthma, diseases of the large intestine, rheumatoid diseases such as rheumatoid arthritis, maculopapular erythemas, stomatitis, conjunctivitis, pericarditis, Alzheimer's Disease, multiple sclerosis, the sequelae of AIDS and HIV infection, genito-urinary infections, Chronic Fatigue Syndrome, and Gulf War Syndrome. However, the actual role of mycoplasmas in these various diseases have been difficult to determine, because most of the associations drawn to mycoplasma nfection are based on serologic evidence rather than direct observation of mycoplasmaorganisms in disease lesions. See, Cole, “Mycoplasma interactions with the immune system: implications for disease pathology,” (http://www.compkarori.com/arthritis/pi16002.htm);Cole, “Mycoplasma-induced arthritis in animals: relevance to understanding the etiologies of the human rheumatic diseases,” Rev. Rhum. Engl. Ed.; 66(1 Suppl):45S-49S (1999); and Nicolson et al., “Mycoplasmal Infections in Chronic Illnesses,” (http://www.gulfwarvets.com/article24.htm).
Mycoplasma and chlamydia have both been implicated in vascular disease, but the etiologic relationships have not been confirmed. See, Chen et al., “Carditis associated with Mycoplasma pneumoniae infection,” Am. J. Dis. Child. 140:471-472 (1986); Clyde et al., “Tropism for Mycoplasma gallisepticum for arterial walls,” Proc. Natl. Acad. Sci. U.S.A. 70::1545-1549 (1973); Danesch et al., “Chronic infections and coronary artery disease: is there a link?”, Lancet 350:430-436 (1997); Farraj et al., “Mycoplasma-associated pericarditis, case report,” Mayo Clin. Proc. 72:33-36 (1997); Fu et al., “Middle cerebral artery occlusion after recent Mycoplasma pneumoniae infection,” J. Neurol. Sci. 157:113-115 (1998); Gurfinkel et al., “IgG antibodies to chlamydial and mycoplasmainfection plus C-reactive protein related to poor outcome in unstable angina,” Arch. Inst. Cardiol. Mex. 67:462-468 (1997); Ong et al., “Detection and widespread distribution of Chlamydia pneumoniae in the vascular system and its possible implications,” J. Clin. Pathol. 49:102-106 (1996); Perez et al., “Leukocytoclastic vasculitis and polyarthritis associated with Mycoplasma pneumoniae infection,” Clin. Infect. Dis. 25:154-155 (1997); Taylor-Robinson and Thomas, “Chlamydia pneumoniae in arteries: the facts, their interpretation, and future studies,” J. Clin. Pathol. 51:793-797 (1998). In Maraha et al., “Is Mycoplasma pneumoniae associated with vascular disease,” J. Clin. Microbiol. 38:935-936 (February 2000), it was stated that “in a serological study, in contrast to C. pneumoniae antibodies, M. pneumoniae antibodies are not associated with recurrent events in patients with unstable angina”, citing Gurkinkel et al., supra. Maraha et al. reported that using PCR, they “were unable to detect M. pneumoniae in the great majority of the 103 tested specimens” of atherectomies and degenerative heart valves, and concluded that “the results . . . do not support the hypothesis that M. pneumoniae is an important factor in the development of vascular disease. In contrast, Home et al. have published a correlation between a positive serology for Mycoplasma pneumoniae and atherosclerosis (Home et al., “IgA sero-positivity to Mycoplasma pneumoniae predicts the diagnosis of coronary artery disease,” J. American Coll. Cardiol. 35:321 (abstract) (2000)).
Frequent co-occurrence of mycoplasmawith other microorganisms, such as chlamydia, have been observed in cell proliferation diseases (International Patent Application No. PCT/BR01/00083, filed Jul. 3, 2001 and BR PI 0002989-0, filed Jul. 3, 2001). This association appears to contribute to increasing the virulence of both pathogens. For example, HIV patients, who have positive serology for Mycoplasma penetrans, are in worse clinical health than HIV patients who test negative for Mycoplasma penetrans. See, Blanchard et al., “AIDS-associated mycoplasmas ,” Annu. Rev. Microbiol., 48:687-712, (1994). Mycoplasmal lipoproteins are potent macrophage activators and have comparable activity and equally wide-spread in mollicutes as is LPS in Gram-negative bacteria. See, Razin et al. Eds., Molecular biology and pathogenicity of mycoplasmas, Kluwer Academic/Plenum Publishers (New York, 2002). Recently described different toll-like receptors (TLR) in macrophages that are activated by products from pathogens such as mycoplasmal lipoproteins and LPS from bacteria have demonstrated to be important for activation of the immune system and that the efficacy of immune response depends on which concomitant TLR s are activated. See, Akira et al., “Toll-like receptors: critical proteins linking innate and acquired immunity,” Nature Immunol. 2:675-680(2001).
Archaea are the most ancient microorganisms existing in nature, but have been characterized only recently. See, Woese et al., “Phylogenetic structure of the prokaryotic domain: the primary kingdoms,” Proc Natl. Acad. Sci. U.S.A. 74: 5088-5090 (1977). They inhabit extreme environments and are constituted by lipid monolayer membranes. Rich alkaline atmosphere with sodium ions and metals prevents proliferation of other bacteria, but is favorable to archaea's growth. Archaea have been isolated from alkaline waters from the Dead Sea, the Great Salt Lake and Yellowstone National Park. They have a small size, can—just barely—be viewed with an optical microscope, and observation of structural details requires electron microscopy. See, Howland et al., The surprising archaea. Discovering another domain of life, Oxford University Press (New York, 2000). Some are considered hyperthermophilic as they survive in very high temperatures.
Another unusual characteristic of some archaea is that they appear to use metal as an energy source. See, Amend et al., “Energetics of overall metabolic reactions of thermophilic and hyperthermophilic Archaea and bacteria,” F.E.M.S. Microbiol. Rev. 25: 175-243 (2001). It is considered that archaea usually need an anaerobic or nearly anaerobic environments to carry out oxidation-reduction reactions with participation of different chemical compounds, including metals. See, Amend et al., “Energetics of overall metabolic reactions of thermophilic and hyperthermophilic Archaea and bacteria,” F.E.M.S. Microbiol. Rev. 25: 175-243 (2001).
Recently, a new kind of extremely small archaea, which is dependent on bigger archaea, was described and named nanoarchaea. See, Huber J et al., “A new phylum of Archaea represented by a nanosized hyperthermophilic symbiont,” Nature 417: 63-67 (2002). With the exception of archaea that reside in the mammalian intestine and produce methane gases, there is no report of archaea existing within plants or animals. See, Florin T H J et al., “Shared and unique environmental factors determine the ecology of methanogens in humans and rats,” Am. J. Gastroenterol. 95: 2872-2879 (2000).